Studies suggest that tumor necrosis factor alpha (TNF-alpha) plays a role in burn pathogenesis. We conducted a randomized controlled experiment in swine to determine whether a novel macrophage inhibitor, semapimod (formerly known as CNI-1493), would blunt the local production of TNF-alpha, interleukin (IL)-1, and IL-6 in burns leading to less injury extension and faster re-epithelialization. After creating second-degree burns, animals received one or two intravenous boluses of semapimod 1 mg/kg or normal saline, and all burns were treated with silver sulfadiazine. The depth of follicular necrosis and thrombosis was reduced by either one or two doses of semapimod (P=.04 and .02, respectively). However, no differences were noted between groups in cytokine levels. Depth of scarring was similar in all groups. We conclude that Semapimod reduces the depth of follicular necrosis and thrombosis after second-degree burns in swine, indirectly resulting in more rapid re-epithelialization. However, this affect does not appear to be mediated by reduced local TNF-alpha, IL-1, or IL-6 protein levels.